氧化损伤白蛋白诱导肾内肾素-血管紧张素系统活化的作用及其机制研究

Accumulation of advanced oxidation protein products (AOPPs), has been well recognized in chronic kidney disease (CKD), and might be involved in the progression of CKD. However, the mechanism underlying the pathobiologic effect of AOPPs remains further investigation. It has been demonstrated that, the kidney, particularly renal tubular epithelial cell, expresses all of the RAS components. Activation of intrarenal renin-angiotensin system (RAS) is critical in the progression of CKD. Our previous study found that chronic AOPPs-modified albumin (AOPPs-albumin) loading in unilateral nephrectomy rats resulted in AOPPs deposition in renal tubular cells accompanied with local RAS activation. The triggering effect of AOPPs-albumin was 100-times stronger than that of unmodified albumin. Therefore, we hypothesized that (1) AOPPs-albumin might be an important trigger of RAS in renal tubular epithelial cells. (2) The triggering effect of AOPPs-albumin was mediated by a signaling pathway distinct from that of unmodified albumin. In this study, we plan to confirm the effect of AOPPs-albumin on RAS activation in renal tubular cells, and to explore the receptors and intracellular signal pathway involved in this process from in vitro and in vivo. Given that AOPPs accumulation is prevalent in CKD, this finding might be highly significant because it might be an important step toward understanding the renal pathogenic effects of AOPPs and may provide new targets for the prevention of progressive CKD.

氧化损伤白蛋白潴留是慢性肾脏病（CKD）的常见特征并与CKD进展密切相关。但其促进CKD进展的机制尚未阐明。肾脏、尤其是肾小管上皮细胞表达完整的肾素-血管紧张素系统（RAS），肾脏RAS活化是CKD进展的重要环节。我们前期研究发现，氧化损伤白蛋白慢性负荷使其在肾小管局部沉积并伴有肾内RAS活化，其作用比正常白蛋白负荷强100倍。故本项目假设：氧化损伤白蛋白潴留是肾小管上皮细胞RAS活化的重要促发因素；氧化损伤白蛋白可能通过与正常白蛋白不同的途径活化肾内RAS。项目拟通过肾小管上皮体外细胞培养和氧化损伤白蛋白慢性负荷模型（1）证实氧化损伤白蛋白导致肾小管上皮细胞RAS活化的病理生物学作用；（2）证实氧化损伤的白蛋白是比正常白蛋白更强的诱导肾内RAS活化的因素；（3）揭示氧化损伤白蛋白活化肾小管上皮细胞RAS的受体途径和细胞内信号调控。为了解蛋白质氧化损伤在CKD进展中的作用及其机制提供新信息

氧化损伤白蛋白（AOPP）潴留和盐敏感状态是慢性肾脏病（CKD）的常见特征并与CKD进展密切相关。但其促进CKD进展的机制尚未阐明。肾脏、尤其是肾小管上皮细胞表达完整的肾素-血管紧张素系统（RAS），肾脏RAS活化是CKD进展的重要环节。本项目旨在阐明氧化损伤白蛋白和高盐在慢性肾脏病RAS活化中的作用和机制，并为干预提供新靶标。主要成果：1. 发现氧化损伤白蛋白AOPP促进慢性肾损伤的新途径：AOPP潴留是肾小管上皮细胞RAS 活化的重要促发因素；AOPP通过肾小管上皮细胞清道夫受体CD36和RAGE介导的，NADPH氧化酶依赖的细胞内信号通路，活化肾内RAS，促进CKD进展。本研究提示减少AOPP生成、阻断AOPP对肾小管上皮细胞的相互作用或其细胞内信号通路可能成为今后干预的新靶标。2. 发现高盐摄入导致慢性肾损伤的新途径：高盐摄入反向活化肾内和脑内RAS，这种活化与全身RAS和血压无关；高盐摄入通过肾脏传入和传出交感神经相互作用 (intercommunication)，同时活化脑内和肾内RAS和氧化应激（ROS）。高盐所致的RAS和ROS在肾内和脑内的共同活化通过交感神经反射弧形成病理正反馈环。这种新发现的反射现象 (reflex phenomenon) 促进慢性肾纤维化。本研究揭示了CKD时盐敏感的机制，为干预盐敏感状态相关疾病提供新视角；揭示了CKD时器官间对话的机制及其在CKD进展中的作用，有助于从整体视角深入理解CKD进展的病理生理基础；阐明高盐饮食导致CKD进展的发病机制，可为制定相关国家卫生政策提供重要依据。项目在包括Antioxid Redox Signal和J Am Soc Nephrol 等国内外期刊发表论著4 篇，其中IF 7以上SCI收录期刊2 篇，国内核心期刊2篇。

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